Download screening for adverse drug interactions in dermatology patients

Trakia Journal of Sciences, Vol. 8, Suppl. 2, pp 266-271, 2010
Copyright © 2009 Trakia University
Available online at:
http://www.uni-sz.bg
ISSN 1313-7050 (print)
ISSN 1313-3551 (online)
SCREENING FOR ADVERSE DRUG INTERACTIONS IN DERMATOLOGY
PATIENTS
M. Ganeva1*, T. Gancheva2, Iv. Baldaranov2, J. Troeva2, E. Hristakieva2
1
Section of Pharmacology and Clinical Pharmacology, Faculty of Medicine, Thracian University
2
Clinic of Dermatology and Venereology, University Hospital,
Faculty of Medicine, Thracian University, Stara Zagora, Bulgaria
ABSTRACT
PURPOSE. To perform a screening for potential adverse drug interactions (DIs) in patients
hospitalized in the Clinic of Dermatology and Venereology at the University Hospital in Stara
Zagora using available electronic resources, and identify the factors associated with their occurrence.
PATIENTS AND METHODS. All consecutive inpatients admitted to the Clinic for the period
March-September 2009 were screened for potential adverse DIs using an electronic drug interactions
checker. Adverse DIs were classified into the following categories: “caution advised”,
“monitor/modify therapy”, “avoid/use altenative” according to clinical management.
RESULTS. A total of 157 patients were included in the study. Adverse DIs (77 in number) were
detected in 40 patients. DIs from the category “Monitor/modify” were the prevalent type. The
development of adverse DIs was significantly associated with a higher number of drugs (p=0.0001)
and old age (p=0.0001). In two cases the adverse DI led to a manifest adverse drug reaction.
DISCUSSION. Adverse DIs were found in a significant part of dermatology patients. The study
confirmed the role of polypharmacy for DIs. Although adverse DIs rarely result in manifest ADRs,
these ADRs can be of high clinical importance due to their severity thus justifying close monitoring
for potential DIs.
Key words: drug interaction, adverse drug reaction
INTRODUCTION
Potential drug interactions (DIs) represent an
important risk factor for the development of
adverse drug reactions (1). A prospective study
of adverse drug reactions (ADRs) from the UK
showed that 16.6% of ADRs leading to
hospital admission are associated with DIs (2).
Pharmacological drug groups of particular
significance for dermatologists considering
their potential for DIs are “general
antiinfectives”
including
antibacterials,
antimycotics, antivirals and “antihistamines”
(3). The high incidence of concomitant
diseases in dermatology patients (4) presumes
a high probability of potential DIs of drugs
pertaining to various pharmacological groups
_____________________________
*Correspondence to: Maria Ganeva, MD, Section
of Pharmacology and Clinical Pharmacology,
Faculty of Medicine, Thracian University, 11
Armeiska St, 6000 Stara Zagora, Bulgaria Tel.:
042664/310, E-mail: [email protected]
266
like cardiovascular drugs, drugs affecting the
central nervous system etc.
The detection and clinico-pharmacological
assessment of adverse DIs require the use of
specialized informational resources and time.
The difficulties in identifying adverse DIs has
led to the development and introduction of
various screening programmes which differ as
to the quantity of information they give (5).
The aim of the present study is to perform a
screening for potential adverse DIs of the
medication prescribed to patients hospitalized
in the Clinic of Dermatology and Venereology
at the University Hospital in Stara Zagora
using available electronic resources, and
identify the factors associated with their
occurrence in this cohort of patients.
Trakia Journal of Sciences, Vol. 8, Suppl. 2, 2010
PATIENTS AND METHODS
Patient population
The investigation is a part of a prospective
pharmacovigilance study carried out among
patients admitted to the Clinic of Dermatology
and Venereology at the University Hospital in
Stara Zagora. All consecutive inpatients
admitted to the Clinic for the period MarchSeptember 2009 were screened for potential
adverse DIs. Information on systemic
medication was collected on the day of
admission and the medical charts were
followed for further changes during the period
of hospitalization. Data were recorded and
checked for adverse DIs using a drug
interactions
checker
(https://online.epocrates.com). For each patient
additionally the following data were recorded:
demographic
characteristics,
primary
diagnosis, concomitant diseases, history of
previous ADRs, alcohol abuse, smoking,
failure of excretory organs.
ADRs resulting from adverse DIs were
recorded in a structured form containing
further information on drug history covering
the last three months preceding hospitalization,
clinical description of the adverse event,
laboratory tests and reviews of consultants.
Definition of DIs
DIs were defined according to Ritter et al., (6)
as the modification of the action of one drug
by another as a result of one or more of three
different
kinds
of
mechanisms:
pharmaceutical,
pharmacodynamic
and
pharmacokinetic. DIs may be beneficial or
harmful (adverse DIs). Adverse DIs were
classified into the following categories:
“caution advised”, “monitor/modify therapy”,
GANEVA M., et al.
“avoid/use
altenative”
(https://online.epocrates.com) according to
clinical management. The DI checker lists for
each interaction the expected or possible
effects of the drug combination, and the
proposed mechanism of interaction.
Definition of ADRs
ADRs were defined according to WHO (7).
Statistical analysis. Descriptive statistics and
Chi-square test were applied. Continuous
variables were tested for normality using
Kolmogorov-Smirnov test. Because the study
values were not normally distributed, the
results were presented as median and
interquartile range (25th–75th percentile). The
non-parametric Mann-Whitney U test was used
to determine between-group differences. A
value of p<0.05 was considered statistically
significant. Analyses were performed using
SPSS for Windows version 9.0.
RESULTS
1. Patient characteristics (Table 1)
A total of 157 patients, 89 female and 68 male
with an age range 1-86 years (median: 52;
interquartile range: 36- 63) were included in
the study. The main causes for hospitalization
by primary diagnosis coded by the
International Classification of Diseases version 10 were infectious dermatoses “L00L08” (36.3%) and eczema/dermatitis “L20L30” (30.6%). Concomitant disease states
were detected in 98 cases (62.4%).
Cardiovascular diseases were diagnosed in 59
patients (37.6%) and were the most frequent
type of concomitant diseases. Endocrine
disorders in 19 patients (12.1%) were second
ranking concomitant diseases following
cardiovascular.
Таble 1. Characteristics of the patient population
Characteristic
Number of pts (%)
Pts with adverse DIs (%*)
Age above 65 years
36 (22.9%)
17 (42.5%)
Female
Drinker
Smoker
Previous ADR
89 (56.7%)
11 (7.0%)
11 (7.0%)
20 (12.7 %)
25 (62.5%)
1 (2.5%)
2 (4.8%)
9 (22.5%)
Excretory organ failure
1 (0.6%)
0 (0%)
pts – patients; % - percent of total; %*- percent of pts in the respective group
2. Adverse DIs (Table 2, Table 3)
Adverse DIs occurred in 40 patients - 15 male
and 25 female with an age range 15-83 years
(median: 61; interquartile range: 55.25 – 68.0).
The total number of detected adverse DIs was
77. In 19 cases the patient had more than one
DI, either from one or from different DI types,
Trakia Journal of Sciences, Vol. 8, Suppl. 2, 2010
267
the maximum number of adverse DIs per
patient being 6.
Adverse DIs marked as ”Avoid/use
alternative” included drugs from various
groups
- antiaggregants, anticoagulants,
diuretics, antidiabetic agents, antiinfectives,
etc. (Table 3). They were result mainly of
additive effects: increased risk of bleeding
(aspirin-anticoagulants), increased risk of
ototoxicity and nephrotoxicity (amikacinfurosemide), CNS depression (clonazepamvalproate). Antagonistic effects on glucose
metabolism and lipids were found in DIs like
bisoprolol-insulin
and
fenofibratehydrochlorothiazide.
DIs from the category “Monitor/modify” were
the prevalent type of DIs (Tables 2, 3).With
only single exceptions all of them included
some cardiovascular preparation (diuretic,
Таble 2. Adverse DIs - distribution by type
Adverse DI type
Number of pts (%)
Caution advised
15 (37.5%)
Monitor/modify therapy
26 (65.0%)
Avoid/use alternative
7 (17.5%)
Total
40
Eight patients had more than one type of adverse DI.
GANEVA M., et al.
beta-blocker, ACE-inhibitor, etc.). The
expected ADR resulting from the most
common DI in the group “ACE-inhibitor plus
diuretic” (13 cases, 16.9% of all DIs) was
hypotension. Hypokalemia was expected to
develop from DIs like digoxin plus thiazides (3
cases), furosemide plus thiazides (4 cases),
thiazides plus glucocorticosteroids (2 cases).
DIs necessitating caution (Table 3) included
preferentially
H1-blockers,
glucocorticosteroids,
calcium-channel
blockers. Combinations of various H1-blockers
(5 cases) due to additive effects increase the
risk of CNS depression. What is more the same
effect is expected from H1-blockers interacting
with other drugs suppressing CNS like
clonidine (3 cases), benzodiazepine (1 case),
etc. Generally CNS depression was due from
12.9% of all DIs.
Number of adverse DIs (%)
18 (23.4%)
52 (67.5%)
7 (9.1%)
77
Таble 3. Adverse DIs - pairs of drugs and number of cases
Avoid/
fenofibrate-hydrochlorothiazide; aspirin-nadroparin; aspirin-clopidogrel;
use altenative amikacin-furosemide (2); bisoprolol-insulin; clonazepam-valproate
Monitor/
fenofibrate-glimepiride; glimepiride-hydrochlorothiazide; glimepiride-indapamide;
modify
glimepiride-metformin (2); hydrochlorothiazide-metformin;
indapamide-metformin (3); hydrochlorothiazide-valsartan; indapamide-telmisartan
(2); indapamide-lisinopril; indapamide-enalapril (3);
indapamide-perindopril; furosemide-perindopril (2); atorvastatin-verapamil;
lovastatin-verapamil; simvastatin-dilthiazem; clonidine-diltiazem; clonidineverapamil (2); metoprolol- timolol; hydrochlorothiazide-fosinopril;
hydrochlorothiazide-perindopril; hydrochlorothiazide-enalapril (2); bisoprololdigoxin (3); digoxin-hydrochlorothiazide; digoxin-furosemide; digoxin-indapamide;
furosemide-indapamide; furosemide-hydrochlorothiazide/triamteren (2); furosemidehydrochlorothiazide; indapamide-salbutamol; ketoconazole-verapamil; amiodaronehydrochlorothiazide; enalapril-triamterene; perindopril-triamteren-spironolacton;
amikacin-cefuroxime; digoxin-tetracycline; metformin-methylprednisolone;
metformin-ranitidine; hydrochlorothiazide-methylprednisolone (2)
Caution
clonidine-cyproheptadine (3); cyproheptadine-levocetirizine (4); aspirin-verapamil
advised
(2); ranitidine-verapamil; clemastine-cyproheptadine; aspirin-methylprednisolone;
bisoprolol-salbutamol; prednisolone-verapamil; fluconazole-methylprednisolone;
clonazepam-cyproheptadine; isosorbide dinitrate-verapamil; hydroxizine-maprotiline
268
Trakia Journal of Sciences, Vol. 8, Suppl. 2, 2010
GANEVA M., et al.
inhibition of digoxin inactivation by
gastrointestinal flora (digoxin-tetracycline); 3)
decreased renal excretion of drugs by
competition for active tubular transport
(metformin-ranitidine, ranitidine-verapamil).
Pharmacodynamic mechanisms were involved
in most of the detected adverse DIs. Additive
effects explain the increased risk of
bradycardia and AV-block (bisoprololdigoxin), of central nervous system depression
(cyproheptadine-levocetirizine, clonazepamcyproheptadine, clonidine-cyproheptadine, etc)
of increased risk of bleeding (aspirinclopidogrel). Synergistic effects are the reason
for increased risk of hypotension with various
combinations of antihypertensive drugs like
ACE-inhibitors or angiotensin receptor
blockers plus diuretics (indapamide-lisinopril,
indapamide-telmisartan, etc). Antagonistic
effects were found in some adverse DIs
(bisoprolol-salbutamol,
indapamidemetformin, fenofibrate-hydrochlorothiazide).
In some cases the underlying mechanism of
adverse DIs remains unknown - increased
bleeding time due the combination aspirinverapamil, increased risk of absence seizures
when receiving clonazepam plus valproate.
Pharmacokinetic mechanism of adverse DI
included: 1) inhibition of hepatic metabolism
and consequent increase of drug levels and risk
of adverse effects of glucocorticosteroids
(fluconazole-methylprednisolone,
dehydrocortisone-verapamil), of antilipemic
agents (atorvastatin-verapamil, lovastatinverapamil, simvastatin-dilthiazem),
of
glimepiride (fenofibrate-glimepiride) and of
verapamil
(ketoconazole-verapamil);
2)
The development of adverse DIs was
significantly associated with a higher number
of drugs (p=0.0001) and old age (p=0.0001).
The clinico-pharmacological risk factors
female sex, excretory organ failure, smoking
and alcohol consumption were not linked to
adverse DIs. The history of previous drug
reaction was associated with adverse DIs
(χ=4.237; p=0.04).
The patients with adverse DIs received from 2
to 10 drugs per patient, median 6.5
(interquartile range 5.0 - 8.0) Patients without
adverse DIs had median drug number per
patient 2.0 (interquartile range 1.0 - 4.0) and
received from 0 to 7 drugs per patient (fig.1)
30
26
25
23
Patients (%)
20
18
15
15
13
10
10
10
8
10
10
DI
7
no
3
3
3
0
0
1
2
3
4
5
6
3
7
8
9
yes
10
Number of drugs/pat ient
Fig. 1 Distribution of patients according to the number of drugs per patient
Trakia Journal of Sciences, Vol. 8, Suppl. 2, 2010
269
3. ADRs
For the six-month study period 6 ADRs were
recorded. In two of these cases an underlying
adverse DI was identified: 1) hypotension in a
70-year old female with arterial hypertension
and atrial flutter receiving a combination of
ACE-inhibitor (enalapril, Enap® 40 mg daily),
beta-blocker (metoprolol, Betaloc Zok® 50 mg
daily) and diuretic (indapamide, Rawel SR®
1.5 mg daily); 2) melena in a 68-year old male
with a history of chronic gastritis and
myocardial infarction on medication with a
beta-blocker, ACE-inhibitor, antilipemic agent,
clopidogrel and aspirin who had received a 4day NSAID treatment for radiculitis and a 2day parenteral methylprednisolone application
120 mg daily for drug-induced urticaria prior
to hospitalization.
DISCUSSION
Adverse DIs were found in a significant part of
the patients hospitalized in the Clinic of
Dermatology - 40 patients that constituted
25.5% of the study population. Other similar
studies using various computerized screening
methods have identified much higher
proportions of patients with DIs - 49,7 % in the
study of Cruciol-Souza and Thomson (8), 66 %
in the study of Blix et al. (9). However in these
investigations
specialized
clinicopharmacological software for detecting
potential DIs was used.
Most common were the DIs requiring careful
monitoring of the prescribed medications or
modification of the dosage regimen. The
prevalent drugs in this category were
cardiovascular drugs which were combined for
therapeutic advantage (ACE-inhibitor plus
diuretic, combination of 2 diuretics, etc.). One
of these DIs resulted in a clinically overt ADR
presented as hypotension which required
withdrawal of the diuretic and a lower dosage
of the ACE-inhibitor. The combination
enalapril-indapamide increases the risk of
hypotension due to synergistic effects.
Second ranking in incidence were mild DIs
requiring caution in drug use. These DIs are
typical for this cohort of patients since they
included drug classes like H1-blockers and
glucocorticosteroids which are commonly
prescribed in dermatology.
Adverse DIs marked as ”Avoid/use
alternative” were 9.1% of all DIs. In one case
the DI including high risk drugs such as aspirin
and clopidogrel due to additive effects led to a
270
GANEVA M., et al.
clinically manifest severe ADR - melena which
was associated with additional treatment and
prolongation of hospitalization. High doses of
methylprednisolone and a NSAID have also
contributed
to
the
development
of
gastrointestinal bleeding in this case. Although
adverse DIs rarely result in manifest ADRs
(10), these ADRs can be of high clinical
importance (2, 11) due to their severity thus
justifying close monitoring of medications for
potential DIs.
The study confirmed the role of polypharmacy
for DIs. High morbidity and number of drugs
in the elderly explain the association of DIs
with old age. The chronicity of concomitant
cardiovascular diseases, and the use of highrisk drugs like diuretics for their treatment may
be the reason why DIs were significantly
associated with the factor “history of previous
ADR”.
Identifying clinically relevant adverse DIs as a
risk factor for the development of ADRs and
appropriately
intervening
in
patients`
therapeutic management is a method of
preventing ADRs in hospitalized patients. This
can be achieved through the joined efforts of
clinicians and clinical pharmacologists.
Computerized screening is essential in quickly
idendifying and controlling DIs as a risk factor
for ADRs and thus assuring the safe use of
drugs.
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